In spite of the many alterations in cell physiology that generally accompany the malignant state, many tumors retain certain normal regulatory mechanisms. Thus, about 30% of patients with metastatic breast cancer respond to ovariectomy, adrenalectomy or hypophysectomy with objective evidence of tumor regression, suggesting that the continued proliferation of the cells of those malignancies required continuous estrogenic stimulation. In support of this, a second study showed that most neoplasms that do not show the presence of the cytoplasmic estradiol receptor, do not respond to endocrine therapy, while most neoplasms that do contain the receptor, and therefore should be able to respond to the presence of estrogen, do respond to endocrine therapy. Such tumors, therefore, appear to recognize and, indeed, require the same signals that act during the normal estrus cycle to induce the controlled hypertrophy and hyperplasia of the healthy uterus. We feel that study of these tumors, with their vestige of normal growth control will provide an important handle to dissect the nature of hormone-responsive and non-responsive tumor growth. Our first objective is to examine the nature and specificity of interaction of the estradiol-receptor complex with the components of chromatin, which we tentatively assume to be the nuclear hormone acceptor. Secondly, we wish to apply this information to an analysis of human and other mammalian endocrine tumors that do or do not respond to endocrine therapy. These studies will test our specific hypothesis that the repeated DNA sequences conspicuously present only in eukaryotic chromosomes have a role in the recognition and binding of the estradiol- receptor complex; and that this recognition and binding system may be altered in some mammary cancers.